PPP1R3F variants impair brain energy metabolism: a novel X-linked cause of neurodevelopmental disorders with translational therapeutic implications

PPP1R3F variants impair brain energy metabolism: a novel X-linked cause of neurodevelopmental disorders with translational therapeutic implications | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article PPP1R3F variants impair brain energy metabolism: a novel X-linked cause of neurodevelopmental disorders with translational therapeutic implications Yimeng Qiao, Hui Gao, Yanan Wu, Yumeng Wang, Yangong Wang, Luxiang Yang, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7948090/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Neurodevelopmental disorders (NDDs) are highly heterogeneous, and their genetic and metabolic underpinnings remain incompletely understood. PPP1R3F encodes a glycogen-targeting subunit of protein phosphatase 1 with poorly defined functions in the brain. Methods We identified novel PPP1R3F variants in two unrelated male patients with intellectual disability and seizures. To investigate pathogenic mechanisms, we combined transcriptomic profiling, cellular metabolic assays, and a PPP1R3F knockout (KO) mouse model. Results Transcriptomic analysis revealed enrichment of differentially expressed genes in energy metabolism pathways. Patient-derived and KO cell models exhibited impaired mitochondrial function, increased reactive oxygen species (ROS) production, and heightened vulnerability to oxygen–glucose deprivation. Consistent with these findings, PPP1R3F KO mice displayed metabolic alterations and deficits in cognition function. Conclusion Our study demonstrates that PPP1R3F loss of function disrupts neuronal energy metabolism and redox balance, providing a novel X-linked genetic cause of NDDs. These findings highlight bioenergetic dysfunction as a mechanistic link between genetic mutations and neurodevelopmental impairment, suggesting energy metabolic modulation as a potential therapeutic avenue. PPP1R3F Energy metabolism Oxygen-glucose deprivation Neurodevelopmental disorders Full Text Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7948090","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":537893228,"identity":"e6ef6a4b-3010-4d68-9e44-5aa927593366","order_by":0,"name":"Yimeng 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implications","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"PPP1R3F, Energy metabolism, Oxygen-glucose deprivation, Neurodevelopmental disorders","lastPublishedDoi":"10.21203/rs.3.rs-7948090/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7948090/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eNeurodevelopmental disorders (NDDs) are highly heterogeneous, and their genetic and metabolic underpinnings remain incompletely understood. PPP1R3F encodes a glycogen-targeting subunit of protein phosphatase 1 with poorly defined functions in the brain.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe identified novel PPP1R3F variants in two unrelated male patients with intellectual disability and seizures. To investigate pathogenic mechanisms, we combined transcriptomic profiling, cellular metabolic assays, and a PPP1R3F knockout (KO) mouse model.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eTranscriptomic analysis revealed enrichment of differentially expressed genes in energy metabolism pathways. Patient-derived and KO cell models exhibited impaired mitochondrial function, increased reactive oxygen species (ROS) production, and heightened vulnerability to oxygen\u0026ndash;glucose deprivation. Consistent with these findings, PPP1R3F KO mice displayed metabolic alterations and deficits in cognition function.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eOur study demonstrates that PPP1R3F loss of function disrupts neuronal energy metabolism and redox balance, providing a novel X-linked genetic cause of NDDs. These findings highlight bioenergetic dysfunction as a mechanistic link between genetic mutations and neurodevelopmental impairment, suggesting energy metabolic modulation as a potential therapeutic avenue.\u003c/p\u003e","manuscriptTitle":"PPP1R3F variants impair brain energy metabolism: a novel X-linked cause of neurodevelopmental disorders with translational therapeutic implications","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-11 18:54:02","doi":"10.21203/rs.3.rs-7948090/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fe8936bd-1caa-41f4-a753-6862e4f2c529","owner":[],"postedDate":"November 11th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-07T16:09:16+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-11 18:54:02","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7948090","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7948090","identity":"rs-7948090","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}